HNF4α is possibly the missing link between epithelial–mesenchymal transition and Warburg effect during hepatocarcinogenesis. Issue 4 (19th December 2022)

• Record Type: Journal Article
• Authors: Shokouhian, Bahare; Negahdari, Babak; Heydari, Zahra; Totonchi, Mehdi; Aboulkheyr Es, Hamidreza; Piryaei, Abbas; Mostafavi, Ebrahim; Vosough, Massoud
• Is Part Of: Cancer science. Volume 114:Issue 4(2023)
• Page Start: 1337
• Page End: 1352
• Publication Date: 2022-12-19
• Subjects: aerobic glycolysis -- epithelial–mesenchymal transition -- hepatocellular carcinoma -- HNF4α overexpression -- Warburg effect; Cancer -- Periodicals; Neoplasms -- Periodicals; Research -- Periodicals; Electronic journals; 616.994005
• DOI: 10.1111/cas.15686
• Languages: English
• ISSNs: 1347-9032

Abstract

Abstract: Hepatocellular carcinoma (HCC) is a heterogeneous, late‐diagnosed, and highly recurrent malignancy that often affects the whole body's metabolism. Finding certain theranostic molecules that can address current concerns simultaneously is one of the priorities in HCC management. In this study, performing protein–protein interaction network analysis proposed hepatocyte nuclear factor 4 alpha (HNF4α) as a hub protein, associating epithelial–mesenchymal transition (EMT) to reprogrammed cancer metabolism, formerly known as the Warburg effect. Both phenomena improved the compensation of cancerous cells in competitive conditions. Mounting evidence has demonstrated that HNF4α is commonly downregulated and serves as a tumor suppressor in the HCC. Enhancing the HNF4α mRNA translation through a specific synthetic antisense long non‐coding RNA, profoundly affects both EMT and onco‐metabolic modules in HCC cells. HNF4α overexpression decreased featured mesenchymal transcription factors and improved hepatocytic function, decelerated glycolysis, accelerated gluconeogenesis, and improved dysregulated cholesterol metabolism. Moreover, HNF4α overexpression inhibited the migration, invasion, and proliferation of HCC cells and decreased metastasis rate and tumor growth in xenografted nude mice. Our findings suggest a central regulatory role for HNF4α through its broad access to a wide variety of gene promoters involved in EMT and the Warburg effect in human hepatocytes. This essential impact indicates that HNF4α may be a potential target for HCC treatment. Abstract : Enhancing the HNF4a mRNA translation through a specific synthetic antisense long non‐coding RNA, profoundly affects both epithelial–mesenchymal transition and onco‐metabolic modules in hepatocellular carcinoma cells. HNF4a overexpression decreased featured mesenchymal transcription factors and improved hepatocytic function, decelerated glycolysis, accelerated gluconeogenesis, and improved dysregulated cholesterol metabolism. Moreover, HNF4a overexpression inhibited the migration, invasion, and proliferation of hepatocellular carcinoma cells and decreased metastasis rate and tumor growth in xenografted nude mice. Our findings suggest a central regulatory role for HNF4a through its broad access to a wide variety of gene promoters involved in the epithelial–mesenchymal transition and the Warburg effect in human hepatocytes. This essential impact indicates that HNF4a may be a potential and novel target for hepatocellular carcinoma.